Bradykinin analogs as selective thrombin inhibitors

Details Bradykinin analogs as selective thrombin inhibitors Bradykinin analogs as selective thrombin inhibitors

1996-07-16

2000-11-07

Low, Christopher S. F.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 13, 514 14, 514 15, 514 16, 514 17, 514 18, 530324, 530325, 530326, 530327, 530328, 530329, 530330, A61K 3816, C07K 1400

Patent

active

061437190

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This invention relates to the inhibition of .alpha.-thrombin-induced and ADP-induced cell activation.


BACKGROUND OF THE INVENTION

Bradykinin is a vasoactive peptide released from the precursor plasma kininogens by kallikrein and other enzymes (Silva et al., Amer. J. Physiol. 156: 261-274 (1949)). Bradykinin has been described to have multiple physiologic functions, including the stimulation of prostacyclin production (Hong, S. L., Thromb. Res. 18, 787 (1980); Crutchley et al., Biochim Biophy Acta 751, 99 (1983)) and the stimulation of the release of plasminogen activators (Smith et al., Blood 66, 835 (1983)). Bradykinin induces superoxide formation and endothelium-dependent smooth muscle hyperpolarization (Holland, J. A. et al., J. Cell Physiol. 143, 21 (1990); Nakashima, M. et al., J. Clin. Invest. 92, 2867 (1993)). Along with acetylcholine, bradykinin is the major inducer of nitric oxide formation (Palmer, R. M. J. et al., Nature 327, 524 (1987)). Bradykinin has been characterized to produce vasodilation in most vascular beds which in the coronary artery circulation results in increased blood flow (Line et al., J. Mol. Cell Cardiol. 24, 909 (1992)). These latter features have led some to characterize bradykinin as a cardioprotective agent (Line et al., supra; Gohlke et al., Hypertension 23, 411 (1994); Parratt et al., Cardiovascular Research 28, 183 (1994); Zanzinger et al., Cardiovascular Research 28, 209 (1994)). Bradykinin's elevation by angiotensin converting enzyme inhibitors is believed to be the mechanism by which these drugs promote their beneficial effects on heart failure.
In addition to the delivery of bradykinin, its parent proteins, high (HK) and low (LK) molecular weight kininogens, also have the ability to be selective inhibitors of .alpha.-thrombin, inhibiting .alpha.-thrombin's ability to activate cells without interfering with its enzymatic ability (Meloni et al., J. Biol. Chem. 266, 6786 (1991); Puri et al., Blood 77, 500 (1991)). This activity was believed to be a unique function for the kininogens; one which had not been ascribed to other proteins. Most naturally occurring human protein inhibitors of .alpha.-thrombin are directed towards its protease activity. HK and LK are selective inhibitors of thrombin's ability to activate platelets by blocking .alpha.-thrombin from binding to the platelet membrane (Meloni et al., supra; Puri et al., supra). This activity of the kininogens appeared to be localized to domain 3 on their heavy chain since isolated domain 3 retains that activity (Jiang et al., J Biol. Chem. 267, 3712 (1992)).
Inhibition of platelet activation by domain 3 is observed by a marked decrease in the platelet's ability to aggregate and secrete their granule contents. The granule contents comprise proteins which participate in hemostasis, thrombosis, and the inflammatory response. Inhibition of endothelial cell activation may similarly be observed by a decrease in secretion of endothelial cell contents such as tissue plasminogen activator and von Willebrand factor.
The domain 3 polypeptide like its parent proteins HK and LK functions to inhibit cell activation by blocking thrombin binding to its target cells. This polypeptide is a selective inhibitor of thrombin-induced platelet activation. Administration of domain 3 therefore does not impact on induction of platelet activation by physiological substances other than thrombin, such as, for example collagen, adenosine diphosphate, epinephrine and platelet activating factor.
Interventional procedures for coronary artery disease such as coronary thrombolysis or percutaneous transluminal coronary angioplasty have made good efforts in reducing mortality from acute coronary thrombosis. However, after intracoronary thrombolysis with lytic agents, the reocclusion rate is high. The major cause for reocclusion is platelet thrombus. When artificial dacron grafts are anastomosed to human arteries, up to 30% of all patients will develop a platelet thrombosis within hours of surgery. This expected high complicat

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Hasan

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